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. 2001 Jan;45(1):23-9.
doi: 10.1128/AAC.45.1.23-29.2001.

Pharmacodynamics of telithromycin In vitro against respiratory tract pathogens

I Odenholt  1 , E Löwdin, O Cars
Affiliations
Free PMC article

Pharmacodynamics of telithromycin In vitro against respiratory tract pathogens

I Odenholt et al. Antimicrob Agents Chemother. 2001 Jan.
Free PMC article

Abstract

Telithromycin (HMR 3647) is a new ketolide that belongs to a new class of semisynthetic 14-membered-ring macrolides which have expanded activity against multidrug-resistant gram-positive bacteria. The aim of the present study was to investigate different basic pharmacodynamic properties of this new compound. The following studies of telithromycin were performed: (i) studies of the rate and extent of killing of respiratory tract pathogens with different susceptibilities to erythromycin and penicillin exposed to a fixed concentration that corresponds to a dose of 800 mg in humans, (ii) studies of the rate and extent of killing of telithromycin at five different concentrations, (iii) studies of the rate and extent of killing of the same pathogens at three different inocula, (iv) studies of the postantibiotic effect and the postantibiotic sub-MIC effect of telithromycin, and (v) determination of the rate and extent of killing of telithromycin in an in vitro kinetic model. In conclusion, telithromycin exerted an extremely fast killing of all strains of Streptococcus pneumoniae both with static concentrations and in the in vitro kinetic model. A slower killing of the strains of Streptococcus pyogenes was noted, with regrowth in the kinetic model of a macrolide-lincosamide-streptogramin B-inducible strain. The strains of Haemophilus influenzae were not killed at all at a concentration of 0.6 mg/liter due to high MICs. A time-dependent killing was seen for all strains. No inoculum effect was seen for the strains of S. pneumoniae, with a 99.9% reduction in the numbers of CFU for all inocula at both 8 h and 24 h. The killing of the strains of S. pyogenes was reduced by 1 log(10) CFU at 8 h and 2 to 3 log(10) CFU at 24 h when the two lower inocula were used but not at all at 8 and 24 h when the highest inoculum was used. For both of the H. influenzae strains there was an inoculum effect, with 1 to 2 log(10) CFU less killing for the inoculum of 10(8) CFU/ml in comparison to that for the inoculum of 10(6) CFU/ml. Overall, telithromycin exhibited long postantibiotic effects and postantibiotic sub-MIC effects for all strains investigated.

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Figures

FIG. 1
FIG. 1
(a) Killing curves for telithromycin at a concentration of 0.6 mg/liter against S. pneumoniae ATCC 6306 (□), S. pneumoniae 1020 (○), S. pneumoniae 2151 (▵). Control strains were S. pneumoniae ATCC 6306 (■), S. pneumoniae 1020 (●), and S. pneumoniae 2151 (▴). (b) S. pyogenes NTCC P1800 (□), S. pyogenes 197 (○), S. pyogenes 138 (▴). (c) H. influenzae NTCC 8468 (□), and H. influenzae CCUG 23969 (○). Controls strains were H. influenzae NTCC 8468 (■) and H. influenzae CCUG 23969 (●).
FIG. 1
FIG. 1
(a) Killing curves for telithromycin at a concentration of 0.6 mg/liter against S. pneumoniae ATCC 6306 (□), S. pneumoniae 1020 (○), S. pneumoniae 2151 (▵). Control strains were S. pneumoniae ATCC 6306 (■), S. pneumoniae 1020 (●), and S. pneumoniae 2151 (▴). (b) S. pyogenes NTCC P1800 (□), S. pyogenes 197 (○), S. pyogenes 138 (▴). (c) H. influenzae NTCC 8468 (□), and H. influenzae CCUG 23969 (○). Controls strains were H. influenzae NTCC 8468 (■) and H. influenzae CCUG 23969 (●).
FIG. 1
FIG. 1
(a) Killing curves for telithromycin at a concentration of 0.6 mg/liter against S. pneumoniae ATCC 6306 (□), S. pneumoniae 1020 (○), S. pneumoniae 2151 (▵). Control strains were S. pneumoniae ATCC 6306 (■), S. pneumoniae 1020 (●), and S. pneumoniae 2151 (▴). (b) S. pyogenes NTCC P1800 (□), S. pyogenes 197 (○), S. pyogenes 138 (▴). (c) H. influenzae NTCC 8468 (□), and H. influenzae CCUG 23969 (○). Controls strains were H. influenzae NTCC 8468 (■) and H. influenzae CCUG 23969 (●).
FIG. 2
FIG. 2
Killing curves for telithromycin against S. pneumoniae 2151 at starting inocula of approximately 104 CFU/ml (□), 106 CFU/ml (■), and 108 CFU/ml (┌) and against S. pyogenes 197 at starting inocula of approximately 104 CFU/ml (○), 106 CFU/ml (●), and 108 CFU/ml (⊕).
FIG. 3
FIG. 3
Killing curves for telithromycin in the in vitro kinetic model. The half-life was 12 h. □, S. pneumoniae ATCC 6306 (Cmax = 0.008 mg/liter); ■, S. pneumoniae 2151 (Cmax = 0.032 mg/liter); ▵, S. pyogenes 197 (Cmax = 0.6 mg/liter); ▾, S. pyogenes 138 (Cmax = 0.6 mg/liter). Controls were S. pneumoniae ATCC 6306 (formula image), S. pneumoniae R-2151 (▹), S. pyogenes 197 (×), and S. pyogenes 138 (✳).
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